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Review : V region gene analysis of human IgM hybridoma monoclonal anti-Sm antibodies

Department of Medicine, Division of Rheumatology, University of Western Ontario, London Health Sciences Centre, University Campus, Department of Microbiology and Immunology, University of Western Ontario, London Health Sciences Centre, University Campus, London, Ontario, N5A 5A5, Canada

JY Edwards

Department of Medicine, Division of Rheumatology, University of Western Ontario, London Health Sciences Centre, University Campus, Department of Microbiology and Immunology, University of Western Ontario, London Health Sciences Centre, University Campus, London, Ontario, N5A 5A5, Canada

DA Bell

Department of Medicine, Division of Rheumatology, University of Western Ontario, London Health Sciences Centre, University Campus, Department of Microbiology and Immunology, University of Western Ontario, London Health Sciences Centre, University Campus, London, Ontario, N5A 5A5, Canada

E. Cairns

Department of Medicine, Division of Rheumatology, University of Western Ontario, London Health Sciences Centre, University Campus, Department of Microbiology and Immunology, University of Western Ontario, London Health Sciences Centre, University Campus, London, Ontario, N5A 5A5, Canada

Anti-Sm antibodies although highly specific for systemic lupus erythematosus can only be found in 10-25% of lupus patients and lupus-prone MRL/lpr mice. Molecular studies of these autoantibodies from mice have suggested that the anti-Sm response is Ag driven, its expression is controlled by stochastic events and may originate from the same B cell precursors as anti-DNA antibodies. However, relatively little information regarding the molecular characteristics of anti-Sm antibodies in man has been reported. We studied the V region genes of three IgM hybridoma monoclonal antibodies (BUD 45.12.8, BUD 114.4.11 and BUD 94.91.8) which were selected for Sm reactivity and derived from B cells of a healthy child. Two of these antibodies BUD 45.12.8 and BUD 114.4.11 also reacted with ssDNA, while the third (BUD 94.91.8) did not. Each of these anti-Sm/ RNP antibodies was encoded by different and predominantly unmutated Ig heavy chain germline genes (BUD 45.12.8 by V_H3-23, DXP4 and J_H4b; BUD 94.91.8 by V_H3-33, D21-9 and J_H6b; BUD 114.4.11 by V_H 1-2, DK1 or DM1 or unknown D and JH4b) and light chain genes (BUD 45.12.8 by Humkv325 and J2; BUD 94.91.8 by hsigg11150 (IIIb) and J2/3; BUD 114.4.11 by Humk18 and J3). Many of these genes are also used by antibodies with other specificities including DNA. The two anti-Sm antibodies which also bound ssDNA shared an overall V region net positive charge, while the third antibody without ssDNA reactivity carried a negative V region net charge. These findings demonstrate that (1) normal individuals have the genetic potential to generate autoantibodies to Sm/RNP; (2) acquisition of Sm/RNP binding is not dependent on somatic mutations and (3) some human B cell clones exhibit specificity for Sm and ssDNA.

Key Words: systemic lupus erythematosus • anti-Sm antibody • V region gene

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